Camptothecin derivatives having antitumor activity

ABSTRACT

Camptothecin derivatives of camptothecin of formula (I)                    
     wherein the groups R 1 , R 2  and R 3  are as defined in the description are disclosed. 
     The compounds of formula (I) are endowed with antitumor activity and show a good therapeutic index. 
     Processes for the preparation of the compounds of formula (I) and their use in the preparation of medicaments useful in the treatment of tumors, viral infections and antiplasmodium falciparum are also disclosed.

The present invention relates to compounds having antitumor activity, inparticular to new derivatives of camptothecins, processes for theirpreparation, their use as antitumor drugs and pharmaceuticalcompositions containing them as active ingredients.

BACKGROUND OF THE INVENTION

Camptothecin is an alkaloid, which was isolated by Wall et al (J. Am.Chem. Soc. 88, 3888-3890 (1966)) for the first time from the treeCamptoteca acuminata, a plant originating from China, of the Nyssaceaefamily.

The molecule consists of a pentacyclic structure having a lactone in thering E, which is essential for cytotoxicity.

The drug demonstrated a wide spectrum of antitumor activity, inparticular against colon tumors, other solid tumors and leukemias, andthe first clinical trials were performed in the early 70's. SinceCamptothecin (in the following briefly CPT) has low water solubility andin order to prepare clinical trials, the National Cancer Institute (NCI)prepared the sodium salt (NSC100880), which is water-soluble. Clinicaltrials in phase I and II, were not completed because of the hightoxicity showed by the compound (hemorrhagic cystitis, gastrointestinaltoxicity, such as nausea, vomit, diarrhoea, and myelosuppression,especially leucopenia and thrombocytopenia.

In any case, sodium salt showed a lower activity than CPT, because, atpH 7.4, the inactive form (open ring) predominates on the lactone-activeone (closed ring), which predominates at pH<4.0.

Subsequently, many CPT analogues were synthesised in order to obtaincompounds with lower toxicity and higher water solubility. Two drugs aremarketed, Irinotecan (CPT-11), marketed with the Trade Mark Camptosar®by Upjohn and Topotecan, marketed with the Trade Mark Hymcamptamin® orThycantin®, by Smith Kline & Beecham. Other derivatives are in differentsteps of clinical development in phase II, such as NSC-603071(9-aminocamptothecin), 9-NC or 9-nitrocamptothecin, an oral prodrugconverted in 9-aminocamptothecin, GG-211 (GI 147211), and DX-8591f, thelatter being water-soluble. All the derivatives identified to datecontain the parent structure with 5 rings, essential for cytotoxicity.It was demonstrated that modifications on the first ring, such as in thecase of the above-mentioned drugs increase water solubility and allow ahigher tolerability of the drug.

Water-soluble Irinotecan was approved for the treatment of many solidtumors and ascites (colon-rectum, skin, stomach, breast, small andnon-small cell lung, cervix and ovarian cancer and in non-Hodgkinlymphoma). Moreover, Irinotecan resulted active in solid tumorsresistant to Topotecan, vincristine or melphalan and MDR-1 cellsresulted marginally resistant to the drug. The active metabolite wasidentified as the 10-hydroxyderivatives (SN-38), produced by the actionof carboxylesterases. CPT-11 showed a good activity using differentadministration routes, such as intraperitoneal, intravenous, oral(Costin D., Potmhexyl M. Advances in Pharmacol. 29B, 51-72 1994).

CPT-11 was administered also with cisplatin or etoposide, showing asynergistic effect, thanks to the ability to hinder DNA repair. Also inthis case, however, a grade 3 and 4 leucopenia and diarrhoea arose(Sinha B. K. (1995) Topoisomerase inhibitors. Drugs 49, 11-19, 1995).

Topotecan has a significant oral bioavailability. Oral administrationproved to be convenient to reach a prolonged exposition to the drug,without the use of temporary catheters being necessary (Rothenberg M. L.Annals of Oncology 8, 837-855, 1997). Also this water-soluble CPTanalogue showed activity against different types of tumors, withdifferent administration routes, intraperitoneal, intravenous,subcutaneous, oral. The more promising results were obtained withTopotecan hydrochloride, intravenous infusion for 5 days, in differenttumors such as small and non-small cell lung, ovarian, breast, stomach,liver, prostatae, soft tissue sarcoma, head and neck, oesophagus,resistant colon-rectum, multiform glioblastoma, chronic and acutemyelocytic leukemias. However, also in this case, severe side effectsoccurred, such as neutropenia and thrombocytopenia, whereasgastrointestinal toxicity, such as nausea, vomit and diarrhoea weremilder.

It was demonstrated that the main transformation and eliminationpathways of the drug comprise lactone hydrolysis and urinary excretion:in fact, lactone form is 50% hydrolysed to open ring, 30 min afterinfusion. Topotecan crosses hematoencephalic barrier 10 min afterinfusion (30% in the cerebrospinal fluid with respect to plasma). On thecontrary, camptothecin does not cross hematoencephalic barrier insignificant amount, probably due to its binding with proteins.

Clinical development of 9-aminocamptothecin was hampered by its scarcewater solubility. Recently, a colloidal dispersion was prepared, whichmade possible its entry in phase II clinical trial. Prolonged exposition(from 72 hours to 21 days) appeared to be essential to demonstrateantitumor activity, because of its short half-life (Dahut et al., 1994).Responses in patients suffering from not treated colon-rectum, andbreast cancer and resistant lymphoma, were noticed. The activitydemonstrated against Pgp-positive tumors suggested a lack ofcross-resistance against resistant MDR-1 cells. Once again, bone marrowand gastrointestinal toxicity was observed.

Lurtotecan is the most water-soluble analogue, with an activitycomparable to Topotecan in vitro. Two regimens were adopted: one 30-mininfusion a day for 5 days every 3 weeks and one 72-hours infusion onetime every 3 weeks. Responses in patients suffering from, neck, ovarian,breast, liver tumour were observed. Also in this case, hematic toxicitywas detected. The molecule is the following:

9-Nitrocamptothecin is an oral prodrug rapidly converted into9-aminocamptothecin after administration. Responses were observed inpatients suffering from pancreas, ovarian, and breast cancer.

Notwithstanding the major part of tumour cells is highly sensitive totopoisomerase I inhibitors, due to the high enzyme levels, some tumorallines result to be resistant. This is due to other mechanisms, ratherthan the overexpression of MDR1 and MRP (multidrug resistance associatedprotein) genes and of their products, P (Pgp) glycoprotein and MRPprotein, respectively, for which Topotecan or CPT-11 are not very goodsubstrates, (Kawato Yet al J. Pharm. Pharmacol. 45, 444-448, (1993)).

In fact, it was observed that some resistant tumour cells contain mutantforms of topo I, accordingly the formation of the topo I-DNA complex isdamaged or some cells lack in the carboxylesterase activity, necessaryfor converting CPT-11 in the active metabolite SN-38 and are thusresistant against this drug (Rothenberg, 1997, ibid.).

Within the drugs used in tumour therapy, the interest in inhibitors oftopoisomerase I enzymes is attributed to the following considerations:a) efficacy against tumors naturally resistant to conventional drugs,topoisomerase II inhibitors included; b) the levels of the topo I enzymeremain elevated in all phases of the cycle; c) many tumors express highlevels of the target enzyme; d) lack of recognition by the proteinsinvolved in the phenomenon of multi-drug resistance (Pgp or MRP) andabsence of the detoxifying enzyme-mediated metabolism, associated to theglutathione-dependent system (glutathione peroxidase and glutathioneS-transferase) (Gerrits C J H., et al., Brit. J. Cancer 76, 952-962).

Once potential clinical advantages of topoisomerase I inhibitors aretaken into consideration, both in terms of antitumor activity, assayedon a wide range of tumors, and the poor induction ofpharmaco-resistance, the present research aims to identify topo Iinhibitors with a lower toxicity with respect to the one demonstrated bythe drugs on the market or in clinical phase. The factors determiningthe relative potency of camptothecin analogues include a) intrinsicactivity of topoisomerase I inhibition; b) drug mean life; c)interaction with plasma proteins; d) the ratio between the circulatingactive form (lactone) and the non active one (carboxylate); e) drugsensitivity relative to cell outflow mediated by glycoprotein P or MRP;f) bond stability with topoisomerase I (Rothenberg, 1997, ibid.).

Among the main adverse effects of Irinotecan and other camptothecinsderivatives, myelosuppression and gastrointestinal toxicity, such asdiarrhoea and vomit, have been observed. Diarrhoea can have an early orlate onset and can be a dose-limiting factor. Vomit and late diarrhoeaare induced by many antitumor drugs, while early diarrhoea occurringduring or immediately after infusion is almost specific for Irinotecanand some camptothecin derivatives.

Toxic effects occur mainly in the intestinal tract.

In order to reduce diarrhoea, CPT-11 was administered in some clinicaltrials, in combination with loperamide, a synthetic oppioid, agonist ofthe mu-oppioid enteric receptors (Abigerges, 1994; Abigerges, 1995), aswell as with an inhibitor of the enkephalinases (acetorfan) or withondansetron, an antagonist of the 5-HT3 receptors, or withdiphenidramine, an antagonist of H1 receptors.

To date, the problems connected with the use of camptothecin derivativesas antitumor drugs can be summarised in the following items:

camptothecin (CPT), and many of its active derivatives have low watersolubility;

the subsequent derivatives are endowed with severe side effects atgastrointestinal and bone marrow level;

some tumour lines developed resistance against topoisomerase Iinhibitors;

there is the constant search for a better therapeutic index.

Patent application WO97/31003, herein incorporated for reference,discloses derivatives of camptothecins substituted at positions 7, 9 and10. Position 7 provides the following substitutions: —CN, —CH(CN)—R₄,—CH═C(CN)—R₄, —CH₂—CH═C(CN)—R₄, —C(═NOH)—NH₂, —CH═C(NO₂)—R₄, —CH(CN)—R₅,—CH(CH₂NO₂)—R₅, 5-tetrazolyl, 2-(4,5-dihydroxazolyl),1,2,4-oxadiazolidin-3-yl-5-one, wherein R₄ is hydrogen, linear orbranched alkyl from 1 to 6 carbon atoms, nitrile, carboxyalkoxy. Ofthese possible compounds, WO97/31003 enables the disclosure only ofcamptothecin derivatives bearing at position 7 the group —CN and—CH═C(CN)₂, with unsubstituted positions 9 and 10.

Of these compounds, the best one proved to be the 7-nitrile (R₄=—CN),hereinafter named CPT 83, with cytotoxic activity on non-small cellslung carcinoma (non-SCLC, H-460). This tumour line is intrinsicallyresistant to cytotoxic therapy and is only moderately responsive totopoisomerase I inhibitors, notwithstanding the overexpression of thetarget enzyme. CPT 83 is more active than Topotecan, taken as referencecompound and on the whole it offers a better pharmacological profile,even in terms of tolerability, then a better therapeutic index.

CPT 83 is prepared through a synthesis route comprising the oxidation of7-hydroxymethylcamptothecin to camptothecin 7-aldehyde, thetransformation of the latter into oxime and final conversion intonitrile.

The starting compound and the intermediates are disclosed in Sawada etal Chem. Pharm. Bull. 39, (10) 2574 (1991). This paper makes referenceto a patent family with priority of 1981, for example European patentapplication EP 0056692, published in 1982, incorporated herein forreference. In these publications there are disclosed, among others, thecompounds camptothecin 7-aldehyde and its oxime. The usefulness of thesederivatives is to provide compounds with antitumor activity having lowtoxicity starting from 7-hydroxymethylcamptothecin. In the paperpublished on Chem. Pharm. Bull. 39, (10) 2574 (1991), the authorsdemonstrate that, with respect to camptothecin, the 7-alkyl and7-acyloxymethyl derivatives, which were not foreseen in the abovementioned patent application, are the more active compounds on lines ofmurine leukemia L1210, while lower activity, always with respect tocamptothecin, was observed in compounds bearing 7-substitutions withhigh polar character, such as hydrazones and the oxime —CH(═NOH).

BRIEF SUMMARY OF THE INVENTION

It has now surprisingly been found that camptothecins bearing analkyloxime O-substituted at position 7 are endowed with antitumoractivity higher than the compound of reference Topotecan. Moresurprisingly, it has been found that camptothecins bearing an enaminogroup on position 7, are also endowed with antitumor activity. Saidcompounds have better therapeutic index.

Accordingly, it is an object of the present invention ompounds ofgeneral formula (I):

Wherein: R₁ is a —C(R₅)═N—O_((n))R₄ group, wherein R₄ is hydrogen or aC₁-C₈ linear or branched alkyl or C₁-C₈ linear or branched alkenyl groupor C₃-C₁₀ cycloalkyl, or (C₃-C₁₀) cycloalkyl-(C₁-C₈) linear or branchedalkyl group, or C₆-C₁₄ aryl, or (C₆-C₁₄) aryl-(C₁-C₈) linear or branchedalkyl group, or a heterocyclic or heterocyclo-(C₁-C₈) linear or branchedalkyl group, said heterocyclic group containing at least one heteroatomselected from the group consisting of nitrogen atom, optionallysubstituted with a (C₁-C₈) alkyl group, and/or oxygen and/or sulfur;said alky, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aryl-alkyl,heterocyclic or heterocyclo-alkyl groups, being optionally substitutedwith one or more groups selected from the group consisting of: halogen,hydroxy, keto, C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, cyano, nitro, —NR₆R₇,wherein R₆ and R₇, the same or different between them, are hydrogen,(C₁-C₈) linear or branched alkyl; the —COOH group or a pharmaceuticallyacceptable ester thereof; or the —CONR₈R₉ group, wherein R₈ and R₉, thesame or different between them, are hydrogen, (C₁-C₈) linear or branchedalkyl, phenyl; or

R4 is a (C₆-C₁₀) aroyl or (C₆-C₁₀) arylsulfonyl group, optionallysubstituted with one or more groups selected from the group consistingof: halogen, hydroxy, C₁-C₈ linear or branched alkyl, C₁-C₈ linear orbranched alkoxy, phenyl, cyano, nitro, —NR₁₀R₁₁, wherein R₁₀ and R₁₁,the same or different between them are hydrogen, C₁-C₈ linear orbranched alkyl;

R₄ is a polyaminoalkyl group; or

R₄ is a glycosyl group;

n is the number 0 or 1;

R₅ is hydrogen, C₁-C₈ linear or branched alkyl, C₁-C₈ linear or branchedalkenyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀) cycloalkyl-(C₁-C₈) linear orbranched alky, C₆-C₁₄ aryl, (C₆-C₁₄) aryl-(C₁-C₈) linear or branchedalkyl;

R₂ and R₃, the same or different between them are hydrogen, hydroxy,C₁-C₈ linear or branched alkoxy; their N₁-oxides, their single isomers,in particular the syn and anti isomers of the —C(R₅)═N—O_((n))R₄ group,their possible enantiomers, diastereoisomers and relative mixtures, thepharmaceutically acceptable salts thereof and their active metabolites;

with the proviso that when R₅, R₂ and R₃ are hydrogen and n is 1, thenR₄ is different from hydrogen.

The present invention comprises the use of the compounds of theabove-mentioned formula (I) as active ingredients for medicaments, inparticular for medicaments useful for the treatment of tumors. A furtherobject of the present invention is also the use of the compounds offormula (I) as active ingredients for medicaments useful for treatingviral infections. Another object of the present invention is also theuse of the compounds of formula (I) as active ingredients formedicaments having antiplasmodium falciparum activity.

The present invention comprises pharmaceutical compositions containingcompounds of formula (I) as active ingredients, in admixture withpharmaceutically acceptable vehicles and excipients.

The present invention comprises also processes for the preparation ofcompounds of formula (I), and the relative key intermediates.

DETAILED DESCRIPTION OF THE INVENTION

Within the scope of the present invention, as examples of C₁-C₈ linearor branched alkyl group, methyl, ethyl, propyl, butyl, pentyl, octyl aremeant and their possible isomers, such as for example isopropyl,isobutyl, tert-butyl.

Examples of C₁-C₈ linear or branched alkenyl group are methylene,ethylidene, vinyl, allyl, propargyl, butylene, pentylene, wherein thecarbon—carbon double bond, optionally in the presence of othercarbon—carbon unsaturations, can be situated in the different possiblepositions of the alkyl chain, which can also be branched within theallowed isomery.

Examples of C₃-C₁₀ cycloalkyl group are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclooctyl, polycyclic groups, such as forexample adamantyl.

Examples of (C₃-C₁₀) cycloalkyl-(C₁-C₈) linear or branched alkyl groupare cyclopropylmethyl, 2-cyclopropylethyl, 1-cyclopropylethyl,3-cyclopropylpropyl, 2-cyclopropylpropyl, 1-cyclopropylpropyl,cyclobutylmethyl, 2-cyclobutylethyl, 1-cyclobutyelthyl,3-cyclobutylpropyl, 2-cyclobutylpropyl, 1-cyclobutylpropyl,cyclohexylmethyl, 2-cyclohexylethyl, 1-cyclohexylethyl,3-cyclohexylpropyl, 2-cyclohexylpropyl, 1-cyclohexylpropyl,5-cyclohexylpentyl, 3-cyclohexylpentyl, 3-methyl-2-cyclohexylbutyl,1-adamantylethyl, 2-adamantylethyl, adamantylmethyl.

Examples of (C₆-C₁₄) aryl, or (C₆-C₁₄) aryl-(C₁-C₈) linear or branchedalkyl group are phenyl, 1- or 2-naphthyl, anthryl, benzyl, 2-phenylethyl1-phenylethyl, 3-phenylpropyl, 2-anthrylpropyl, 1-anthrylpropyl,naphthylmethyl, 2-naphthylethyl, 1-naphthylethyl, 3-naphthylpropyl,2-naphthylpropyl, 1-naphthylpropyl, cyclohexylmethyl, 5-phenylpentyl,3-phenylpentyl, 2-phenyl-3-methylbutyl.

Examples of heterocyclic or heterocyclo-(C₁-C₈) linear or branched alkylgroup are thienyl, quinolyl, pyridyl, N-methylpyperidinyl, 5-tetrazolyl,2-(4,5-dihydroxazolyl), 1,2,4-oxadiazolidin-3-yl-5-one, purine andpyrimidine bases, for example uracyl, optionally substituted as shown inthe general definitions above-mentioned.

Examples of (C₆-C₁₀) aroyl groups are benzoyl, naphthoyl.

Examples of (C₆-C₁₀) arylsulfonyl groups, optionally substituted with analkyl group, are tosyl, benzenesulfonyl. As halogen it is intendedfluorine, chlorine, bromine, iodine.

Examples of substituted groups are pentafluorophenyl, 4-phenylbenzyl,2,4-difluorobenzyl, 4-aminobutyl, 4-hydroxybutyl, dimethylaminoethyl,p-nitrobenzoyl, p-cyanobenzoyl.

Examples of polyaminoalkyl group is—(CH₂)_(m)—NR₁₂—(CH₂)_(p)—NR₁₃—(CH₂)_(q)—NH₂, wherein m, p are aninteger from 2 to 6 and q is an integer from 0 to 6, extremes includedand R₁₂ and R₁₃ are a (C₁-C₈) linear or branched alkyl group, forexample N-(4-aminobutyl-)2-aminoethyl, N-(3-aminopropyl)-4-aminobutyl,N-[N-(3-aminopropyl)-N-(4-aminobutyl)]-3-aminopropyl.

Examples of glycosyl group are 6-D-galactosyl, 6-D-glucosyl,D-galactopyranosyl, the glycosyl group being optionally protected with asuitable ketal group, isopropylidene, for instance.

Examples of pharmaceutically acceptable salts are, in case of nitrogenatoms having basic character, the salts with pharmaceutically acceptableacids, both inorganic and organic, such as for example, hydrochloricacid, sulfuric acid, acetic acid, or, in the case of acid group, such ascarboxyl, the salts with pharmaceutically acceptable bases, bothinorganic and organic, such as for example, alkaline and alkaline-earthhydroxides, ammonium hydroxide, amine, also heterocyclic ones.

A first group of preferred compounds comprises the compounds of formula(I) wherein n is 1.

A second group of preferred compounds comprises the compounds of formula(I) wherein n is 0.

Within the two above mentioned preferred groups, the compounds offormula (I) are preferred, wherein R₄ is different from hydrogen, inparticular is a C₁-C₈ linear or branched alkyl or C₁-C₈ linear orbranched alkenyl group, or C₃-C₁₀ cycloalkyl, or (C₃-C₁₀)cycloalkyl-(C₁-C₈) linear or branched alkyl, or C₆-C₁₄ aryl, or (C₆-C₁₄)aryl-(C₁-C₈) linear or branched alkyl, or a heterocyclic orheterocyclo-(C₁-C₈) linear or branched alkyl group, said heterocyclicgroup containing at least a heteroatom selected from the groupconsisting of nitrogen atom, optionally substituted with a (C₁-C₈) alkylgroup, and/or oxygen and/or sulfur; said alkyl, alkenyl, cycloalkyl,aryl, aryl-alkyl, heterocyclic or heterocyclo-alkyl groups, beingoptionally substituted with one or more groups selected from the groupconsisting of: halogen, hydroxy, C₁-C₈ alky, C₁-C₈ alkoxy, phenyl,cyano, nitro, —NR₆R₇, wherein R₆ and R₇, the same or different betweenthem, are hydrogen, (C₁-C₈) linear or branched alkyl; the —COOH group ora pharmaceutically acceptable ester thereof; or the —CONR₈R₉ group,wherein R₈ and R₉, the same or different between them, are hydrogen,(C₁-C₈) linear or branched alkyl, according to the definitions givenabove by means of example.

A first group of particularly preferred compounds comprises:

7-methoxyiminomethylcamptothecin (CPT 179);

7-methoxyiminomethyl-10-hydroxycamptothecin (CPT 211);

7-(ter-butoxycarbonyl-2-propoxy)iminomethylcamptothecin (CPT 224);

7-ethoxyiminomethylcamptothecin;

7-isopropoxyiminomethylcamptothecin;

7-(2-methylbutoxy)iminomethylcamptothecin;

7-t-butoxyiminomethylcamptothecin (CPT 184);

7-t-butoxyiminomethyl-10-hydroxycamptothecin (CPT 212);

7-t-butoxyiminomethyl-10-methoxycamptothecin (CPT 220);

7-(4-hydroxybutoxy)iminomethylcamptothecin;

7-triphenylmethoxyiminomethylcamptothecin (CPT 192);

7-carboxymethoxyiminomethylcamptothecin (CPT 183),

7-(2-amino)ethoxyiminomethylcamptothecin (CPT 188);

7-(2-N,N-dimethylamino)ethoxyiminomethylcamptothecin (CPT 197);

7-allyloxyiminomethylcamptothecin (CPT 195);

7-cyclohexyloxyiminomethylcamptothecin;

7-cyclohexylmethoxyiminomethylcamptothecin;

7-cyclooctyloxyiminomethylcamptothecin;

7-cyclooctylmethoxyiminomethylcamptothecin;

7-benzyloxyiminomethylcamptothecin (CPT 172);

7-[(1-benzyloxyimino)-2-phenylethyl]camptothecin;

7-(1-benzyloxyimino)ethylcamptothecin (CPT 186);

7-phenoxyiminomethylcamptothecin (CPT 223);

7-(1-t-butoxyimino)ethylcamptothecin;

7-p-nitrobenzyloxyiminomethylcamptothecin (CPT 177);

7-p-methylbenzyloxyiminomethylcamptothecin (CPT 178);

7-pentafluorobenzyloxyiminomethylcamptothecin (CPT 182);

7-p-phenylbenzyloxyiminomethylcamptothecin (CPT 187);

7-[2-(2,4-difluorophenyl)ethoxy]iminomethylcarptothecin;

7-(4-t-butylbenzyloxy)iminomethylcamptothecin;

7-(1-adamantyloxy)iminomethylcamptothecin ;

7-(1-adamantylmethoxy)iminomethylcamptothecin;

7-(2-naphthyloxy)iminomethylcamptothecin;

7-(9-anthrylmethoxy)iminomethylcamptothecin;

7-oxiranylmethoxyiminomethylcamptothecin (CPT 213);

7-(6-uracyl)methoxyiminomethylcamptothecin;

7-[2-(1-uracyl)ethoxy]iminomethylcamptothecin (CPT 199);

7-(4-pyridyl)methoxyiminomethylcamptothecin (CPT 189);

7-(2-thienyl)methoxyiminomethylcamptothecin;

7-[(N-methyl)-4-piperidinyl]methoxyiminomethylcamptothecin (CPT 190);

7-[2-(4-morphoininyl]ethoxy]iminomethylcamptothecin (CPT 210);

7-(benzoyloxyiminoethyl)camptothecin (CPT 191)

7-[(1-hydroxyimino)-2-phenylethyl)camptothecin (CPT 185);

7-ter-butyloxyiminomethylcamptothecin N-oxide (CPT 198);

7-methoxyiminomethylcamptothecin N-oxide (CPT 208);

A second group of particularly preferred compounds comprises:

7-[N-(4-aminobutyl)-2-aminoethoxy]iminomethylcamptothecin;

7-[N-[N-(3-amino-1-propyl)-4-amino-1-butyl]-3-aminopropoxy]iminomethylcamptothecin;

7-(6-D-galactosyloxy)iminomethylcamptothecin;

7-(1,2:3,4-di-O-isopropylydene-D-galactopyranosyloxy)iminomethylcamptothecin(CPT 215);

7-(6-D-glucosyloxy)iminomethylcamptothecin (CPT 216);

A third group of particularly preferred comprises compounds:

7-t-butyliminomethylcamptothecin;

7-(4-amino)butyliminomethylcamptothecin;

7-(4-hydroxy)butyliminomethylcamptothecin (CP 169);

7-(2-N,N-dimethylamino)ethyliminomethylcamptothecin (CPT 171);

7-allyliminomethylcamptothecin;

7-cyclohexyliminomethylcamptothecin (CPT 156);

7-phenyliminomethylcamptothecin (CPT 154);

7-p-nitrophenyliminomethylcamptothecin (CPT 160);

7-benzyliminomethylcamptothecin (CPT 175);

7-(2-anthrylmethyl)iminomethylcamptothecin;

7-(2-quinolylmethyl)iminomethylcamptothecin;

7-(2-thienyl)iminomethylcamptothecin;

7-[N-[N-(3-amino-1-propyl)-4-amino-1-butyl]-3-aminopropyl)iminomethyl-camptothecin;

7-(6-D-galactosyl)iminomethylcamptothecin.

In a first preferred embodiment of the invention, compounds of generalformula (I) are provided, wherein n is 1, therefore camptothecins7-oxime, and R₄ is an alkyl or arylalkyl group, as above defined.

Among these, the highly preferred compounds are:

7-(t-butoxy)iminomethylcamptothecin (CPT 184) of formula

and

7-benzyloxyiminomethylcamptothecin (CPT 172).

The compounds of formula (I) can be prepared with different methodsaccording to the nature of the R₄ group and to the presence of theoxygen atom linked to the nitrogen of the 7-iminomethyl group.

Concerning the compounds of formula (I) wherein n is 1 and R₄ is asabove defined, with the exception of aroyl and arylsulfonyl, can beprepared starting from camptothecin 7-aldehyde (formula Ia, R₅ hydrogen)or 7-keto camptothecin (formula Ia, R₅ different from hydrogen).

Sawada et al Chem. Pharm. Bull. 39, (10) 2574 (1991)), or of a 7-keto byreacting with a halide R₄—X, wherein X is preferably iodine, in a polarsolvent, for example tetrahydrofurane or alcohols, and in the presenceof a base, for example sodium hydride or potassium carbonate.

As to the compounds of formula (I) wherein n is 1 and R₄ is aroyl orarylsulfonyl, as defined for the formula (I), these can be preparedstarting from camptothecin 7-oxime, whose preparation is described inthe previous paragraph, with acyl chlorides R₄—COCl, in polar solvents,and in the presence of a base, preferably pyridine, or directly inpyridine, as disclosed by Cho et al. J. Org. Chem. 62, 2230 (1997).

As far as the compounds of formula (I) wherein n is 0 and R₄ is as abovedefined, with the exception of aroyl, they can be prepared starting fromcamptothecin 7-aldehyde (formula Ia, R₅ hydrogen) or 7-keto camptothecin(formula Ia, R₅ different from hydrogen).

wherein R₁ is the group —C(R₅)═O, and R₅ is as defined for the formula(I), R₂ and R₃ are as defined in formula (I). The compound of formula(Ia) is reacted with the compound of formula (IIa) R₄O—NH₂, wherein R₄is as above defined, to give compounds of formula (I), wherein R₁ is thegroup —C(R₅)═N—OR₄, R₄ is defined as in formula (I), except aroyl andarylsulfonyl. The reaction can be carried out with conventional methodswell known to the person skilled in the art, being a normal formation ofan oxime. Preferably, the molar ratio between 7-aldehyde or 7-ketocamptothecin and hydroxylamine is comprised between 1:3 and 3:1. Thesalts of the hydroxyiamine of interest can also be used. The reaction iscarried out in the presence of a base, for example an inorganic base,such as potassium carbonate, or organic, such as triethylamine ordiazabicyclononene, using polar solvents, preferably methanol or ethanoland carrying out the reaction at a temperature comprised between roomtemperature and boiling point of the solvent used, optionally in thepresence of dehydrating agents, for example sodium or magnesium sulfate,molecular sieves. If desired it is also possible to carry out thereaction in the presence of a catalyst, for example a Lewis acid.

Alternatively, the above compounds can be prepared from the oxime of thecamptothecin 7-aldehyde (obtained as disclosed in

wherein R₁ is the group —C(R₅)═O, and R₅ is as defined for the formula(I), R₂ and R₃ are as defined in formula (I). The compound of formula(Ia) is reacted with the compound of formula (IIb) R₄—NH₂, wherein R₄ isas above, to give compounds of formula (I), wherein R₁ is the group—C(R₅)═N—R₄, R₄ is defined as in formula 1, except aroyl. The reactioncan be carried out with conventional methods well known to the personskilled in the art, being a normal formation of an imine. Preferably,the molar ratio between 7-aldehyde or 7-keto camptothecin and amine iscomprised between 1:3 and 3:1. The salts of the amine of interest canalso be used. The reaction is carried out in the presence of a base, forexample an inorganic base, such as potassium carbonate, or organic, suchas triethylamine or diazabicyclononene, using polar solvents, preferablymethanol or ethanol and carrying out the reaction at a temperaturecomprised between room temperature and solvent boiling point, optionallyin the presence of dehydrating agents, for example sodium or magnesiumsulfate, molecular sieves. If desired it is also possible to carry outthe reaction in the presence of a catalyst, for example a Lewis acid (asdisclosed for example by Moretti and Torre, Synthesis, 1970, 141; or byKobayashi et al, Synlett, 1977, 115).

The camptothecin 7-aldehyde and the camptothecin 7-oxime are disclosedin the patent application EP 0056692 and in the mentioned Sawada et alChem. Pharm. Bull. 39, (10) 2574 (1991),

N₁-oxides of the compounds of formula (I) are prepared according towell-known methods of oxidation of heteroaromatic nitrogen, preferablyby oxidation with acetic or trifluoroacetic acid and hydrogen peroxide,or by reaction with organic peroxyacids (A. Albini and S. Pietra,Heterocyclic N-oxides, CRC, 1991).

Regarding the various meanings of R₄, present in the different reactivesof formula II, these reactives are available in the market, or can beprepared according to well-known methods in literature, which the expertin the field can resort to, completing with their own knowledge of theargument.

Pharmaceutically acceptable salts are obtained with conventional methodsfound in the literature, and do not necessitate of further disclosure.

The compounds disclosed in the present invention show antiproliferativeactivity, therefore are useful for their therapeutical activity, andposses physico-chemical properties that make them suitable to beformulated in pharmaceutical compositions.

The pharmaceutical compositions comprise at least a compound of formula(I), in an amount such as to produce a significant therapeutical effect,in particular antitumoral effect. The compositions comprised within thepresent invention are conventional and are obtained with commonly usedmethods in the pharmaceutical industry. According to the desiredadministration route, the compositions shall be in solid or liquid form,suitable to the oral, parenteral, intravenous route. The compositionsaccording to the present invention comprise together with the activeingredients at least a pharmaceutically acceptable vehicle or excipient.Formulation co-adjuvants, for example solubilizing, dispersing,suspending, emulsionation agents can be particularly useful.

The compounds of formula (I) can also be used in combination with otheractive ingredients, for example other antitumor drugs, both in separateforms, and in a single dose form.

The compounds according to the present invention are useful asmedicaments with antitumor activity, for example in lung tumors, such asthe non-small cell lung tumour, tumors of the colon-rectum, prostate,gliomas.

Cytotoxic activity of the compounds of the present invention was assayedin cell systems of human tumour cells, using the antiproliferativeactivity test as a method of evaluation of the cytotoxic potential.

The cell line used is a lung non-small cell carcinoma that belongs tonon-small cells hystotype named NCI H460.

The preferred compounds 7-(t-butoxyiminomethylcamptothecin (CPT 184) and7-benzyloxyiminomethylcamptothecin (CPT 172) were assayed in comparisonwith Topotecan (TPT), the reference standard accepted by the personsexpert in the field, and with 7-hydroxyiminomethylcamptothecin (CPT181), disclosed by Sawada et al in Chem. Pharm. Bull. 39(10), 2574-2580,(1991), being the closest structural analogue to the compounds offormula (I) according to the present invention.

For the in vivo studies, the solubilization was carried out in 10% DMSOin bidistilled water, being impossible the solubilization in saline, andthe administration for the oral route was carried out at a volume of 10ml/kg.

Antitumoral Activity

Atimic nu/nu Swiss mice (Charles River, Calco, Italia), ageing 10-12weeks were used. The animals were maintained in laminar flow rooms,according to the guidelines of the United Kingdom Co-ordinationCommittee Cancer Research. Experimental protocols were approved by theEthical Committee for animal experimentation of Istituto Nazionale perlo Studio e Cura dei Tumori.

Tumour fragments of about 2×2×2 mm coming from mice to which wereinoculated s.c. 10⁶ cells NCI H460/topo, were implanted s.c. bilaterallyin groups of 5 mice each.

The animals were treated with the compounds when the tumour began to bepalpable, according to the following scheme:

CPT172 (8 mg/kg, po) q4dx4

CPT172 (16 mg/kg, po) q4dx4

CPT172 (24 mg/kg, po) q4dx4

CPT172 (2 mg/kg, po) qdx5×10w

CPT181 (15 mg/kg, po) q4dx4

CPT181 (25 mg/kg, po) q4dx4

CPT184 (2 mg/kg, po) q4dx4

CPT184 (5 mg/kg, po) q10dx6

Topotecan (15 mg/kg, po) q4dx4

Topotecan (10 mg/kg, po) q4dx4

Twice a week, using a Vernier caliper, the width, minimum diameter (l),length and maximum diameter (L) of the tumors were measured, in mm. Thetumour volume (mm³) was calculated according to the formula l²×L/2.Efficacy of the molecule was evaluated as TVI percent of the treatedgroup versus the control group according to the formula TVI%=100−(T/C×100), wherein T is the mean value of the tumour volume of thetreated group and C of control one. A compound is considered active whenTVI %≧50.

The following Table 1 reports the experimental results.

TABLE 1 Antitumoral activity of the camptothecin analogues in thetreatment of the lung carcinoma NCI H460 Dose Toxicity Com- (mg/kg,Treatment Efficacy Body weight pound p.o.) scheme (TVI %) Lethality loss(%) CPT172 8 q4dx4 77 16 q4dx4 88 24 q4dx4 97 0/4 6 2 qdx5x10w 90 0/3 0CPT181 15 q4dx4 40 0/4 0 25 q4dx4 70 0/4 0 CPT184 2 q4dx4 100 0/5 0 5q10dx6 99 0/4 9 TPT 15 q4dx4 94 0/4 0 15 q4dx4 89 0/5 10 10 q4dx4 64 0/50 TVI % was evaluated 5-10 days after the last treatment

CPT172 demonstrated an antitumoral efficacy at different doses and atdifferent treatment schemes; CPT184 revealed to be a very activecompound at low doses and at different treatment schemes, accordingly,both compounds are two particularly promising molecules for clinicalapplication.

Further advantages of these molecules can be identified in the wideinterval of effective doses, indicating an increase of therapeutic indexand a higher handling in the therapeutical use, in particular if aprolonged administration in the time is foreseen, above all in theinjectable formulations, with the use of variable schemes and doses. Forsuch uses, compound CPT 172 appears more favourable in relation to thereduced toxicity.

An important drawback of conventional camptothecins is the reversibilityof the their bond in the ternary complex (drug-DNA-enzyme). Thisreversibility affects drug efficacy, as it does not allow thetransformation of the single strand DNA cleavage into double strand DNAcleavage during DNA synthesis.

Table 2 below shows the persistence of DNA cleavage to a selected numberof in-vitro cleavage sites. After 20 minutes of incubation of the drugin the reaction mixture containing labelled DNA and the purified enzyme,sodium chloride (0,6 M) was added with the scope of assisting thedissociation of the ternary complex. The result, shown in the table aspercentage of DNA cleavage persistence at the sites, examined afterabout 10 minutes, is an indication of an almost complete reversibilityof the cleavages in the case of camptothecin and Topotecan and a markedpersistence in the case of CPT 172 and CPT 184.

TABLE 2 Persistence of DNA cleavage stimulated by camptothecins andmediated by topoisomerase i on selected sites DRUG (10 im) PERSISTENCE(%) Camptothecin 16 Topotecan 16 CPT 181 28 CPT 184 72 CPT 172 80

The advantage offered by the compounds according to the presentinvention is evident in overcoming the limit of reversibility of theternary complex with respect to the state of the art. In preclinicalinvestigations, CPT 184 showed cytotoxic activity in various tumor celllines.

This broad spectrum of anticancer activity was confirmed in micetransplanted with human tumor xenografts, including NSCLC (H460, A549),prostate ca. (JCA-1), glioblastoma (GBM/7), gastric ca. (MKN28),osteosarcoma (U2OS), ovarian ca. (A2780/Dx, A2780/DDP) and colon (HT29,CoBA) carcinomas as well as in murine lung cancer (M109) and leukaemiamodel (L1210).

The preclinical data suggest that CPT 184 may be an active anticanceragent against human's cancers and in particular against non-small celllung cancer (NSCLC), glioblastoma and prostate carcinoma (Table 3).

TABLE 3 Antitumor activity of CPT 172, CPT 184 vs TPT on different tumormodels CPT 184 CPT 172 TPT 2 mg/kg 3 mg/kg 20 mg/kg 25 mg/kg 15 mg/kgH460 99 — — 97 98 (5/8*) HT29 92 — — 88 65 CoBA 84 87 84 93 85 GBM/7 9798 93 98 96  (3/10*) (2/8*) (3/11*) (9/12*) (1/10*) U87 80 87 — — 82A2780 100  — — — 96 (1/8*) A2780/Dx 92 100  — — 92 (1/8*) (8/8*) (2/10*)A2780/DDP 77 90 — — 92 IGROV-1 93 96 — — 89 JCA-1 98 — 98 — 95 (5/8*)DU145 95 — — — 77 L1210 >400*** — — >400** 39

Results are expressed for solid tumors as TVI %=tumor volumeinhibition=100−(tumor weight of treated group/mean tumor weight ofcontrol group×100) and for L1210 as ILS %=percent increase in life span[(MST of treated group/MST of control group)×100]−100.

*no evidence of tumor at the end of the treatment lasting for about 10days from the last administration.

**>50% and***>80% of cured mice alive 120 d from leukemia injection.

H460=NSCLC

HT29 and CoBA=colon ca

IGROV{dot over (-)}1, A2780, A2780/Dx and A2780/DDP=ovarian ca

GBM/7 and U87=glioblastoma

JCA-1 and DU145=prostate ca

L1210=murine leukemia

The high cytotoxic potency of the compounds of the present invention,herein represented in an exemplary way with one of the preferredcompounds, CPT 184, is also reflected by the potent antitumor activity.Using a panel of tumor xenografts characterized by a significantresponsiveness to Topotecan (TPT) (i.e. TVI>80%), the spectrum ofantitumor activity of CPT 184, and in a wide sense by the compounds ofthe present invention, against a significant number of human tumormodels was substantially impèroved. In particular, an impressiveantitumor efficacy was found in the treatment of many tumor models,where complete regressions were achieved in a large number of treatedanimals. Moreover, the compounds of the present invention, in particularthe CPT 184, were able to induce 100% CR in the A2780/DX tumorchracterized by a MDR-phenotype. This observation is of high importance,indicating that the compounds of the present invention are not asubstrate for P-glycoprotein.

Additional therapeutic advantages of the compounds of the presentinvention are related to a) an improvement of the therapeutic index, b)drug efficacy in a large range of doses, c) evidence of efficacy usingquite different schedules, making the compounds of the present inventionless dependent on the treatment schedule than that of Topotecan.

The following examples further illustrate the invention.

EXAMPLE 1 7-benzyloxyiminomethylcamptothecin (CPT 172)

500 mg (1,33 mmoles) of 7-formylcamptothecin were dissolved into 100 mlof ethanol. 15 ml of pyridine and 638 mg (4 mmoles) ofO-benzylhydroxylamine hydrochloride were added and were left for 5 hoursto reflux. The solvent was evaporated under vacuum and the residue soobtained was purified by means of flash chromatography on silica gelusing a mixture of hexane/ethyl acetate 4/6 as eluant.

Yield 65%

m.p.: 200°-205° C. dec.

The obtained product is constituted by an about 8:2 mixture of the twosyn and anti isomers (isomer A: Rf 0.32; isomer B, Rf: 0.19 on silicagel Merck 60 F₂₅₄, eluant hexane/ethyl acetate 3/7).

HPLC: the analyses were carried out on an instrument equipped with aquaternary pump (HP 1050) with Rheodyne injector (20 μl loop) and with adiode array detector (Hp 1050) controlled by a softwareHPLC-ChemStation. Spectra acquisition was made from 200 to 600 nm andthe chromatograms were registered at 360 and 400 nm.

A C18 reverse phase column (Rainin C18; 25×0.4 cm, Varian) was used withan RP18 precolumn. The analysis was carried out with a linear elutiongradient, starting from acetonitrile:water 30:70 to acetonitrile 100% in20 min, with 1 ml/min flow. Retention times were: 12.51 min for isomer Band 14.48 for isomer A.

¹H-NMR (300 MHz; DMSO-d₆): δ: 0.88 (t, H3-18A+H3-18B), 1,87 (m,H2-19A+H2-19B), 5.18 (s, H2-5B), 5.21 (s, H2-PhB), 5.30 (H2-PhA), 5.40(s, H2-5A), 5.45 (s, H2-17A+H2-17B), 6.53 (s, OHA+OHB), 7.3-7.6 (m,ArA+ArB+H-14A+H14B), 7.75 (m, H-11A+H-11B). 7.85-7.95 (m, H10A+H-10B),7.98 (dd, H-12B). 8.18-8.27 (m, H-12A+H9-B), 8.45 (s, CH═NB), 8.59 (dd,H-9A), 9.38 (s, CH═N A).

Mass m/z 481 (M⁺ 100) 374 (30)330(70)300(30)273(20)243(20)91(34).

EXAMPLE 2 7-t-butoxyiminomethylcamptothecin (CPT 184)

400 mg (1,06 mmoles) of 7-formylcamptothecin were dissolved in 80 ml ofethanol. 12 ml of pyridine and 400 mg (3,18 mmoles) ofO-t-butylhydroxylamine hydrochloride were added and left for 4 hours toreflux. The solvent was evaporated under vacuum and the residue soobtained was purified by means of flash chromatography on silica gelusing a mixture of hexane/ethyl acetate 4/6 as eluant. 322 mg (0,72mmoles) of a yellow solid were obtained.

Yield 68%

m.p.: 250° C. dec.

The obtained product is constituted by an about 8:2 mixture of the twosyn and anti isomers (isomer A: Rf 0.31; isomer B. Rf: 0.24 on silicagel Merck 60 F₂₅₄, eluant hexane/ethyl acetate 3/7).

HPLC: the analyses were carried out on an instrument equipped with aquaternary pump (HP 1050) with Rheodyne injector (20 μl loop) and with adiode array detector (Hp 1050) controlled by a softwareHPLC-ChemStation. Spectra acquisition was made from 200 to 600 nm andthe chromatograms were registered at 360 and 400 nm.

A C18 reverse phase column (Rainin C18; 25×0.4 cm, Varian) was used withan RP18 precolumn. The analysis was carried out with a linear elutiongradient, starting from acetonitrile:water 30:70 to acetonitrile 100% in20 min, with 1 ml/min flow. Retention times were: 12.92 min for isomer Band 14.61 for isomer A.

¹H-NMR (300 MHz; DMSO-d₆): δ: 0.88 (t, H3-18A+H3-18B), 1.30 (s,t-but.B), 1.47 (s, t-but.A) 1.87 (m, H2-19A+H2-19B) 5.18 (s, H2-5B),5.37 (H2-5A), 5.42 (s, H2-17A+H2-17B), 6.54 (s, OHA+OHB), 7.35 (s,H-14A). 7.36 (s, H-14B) 7.69-7.83 (m, H-11A+H-11B), 7.85-7.98 (m,H-10A+H-10B), 8.07 (dd, H-9B), 8.16-8.27 (m, H-9A+H-12B) 8.40 (s, CHB),8.62 (dd, H-12A), 9.31 (s, CHA).

Mass m/z 448 (M⁺ 28) 391 (40)374(100)362(40)330(34)57(17).

According to the same procedure the following compounds were prepared:

7-t-butoxyiminomethyl-10-hydroxycamptothecin (CPT 212); m.p. 195 dec.

¹H NMR (DMSO-d₆) δ=0.88 (t, J=7.35 Hz, H₃-18) 1.45 (s, 3 —CH₃) 1.80-1.90(m, H₂-19) 5.12 (s, H₂-5 anti) 5.33 s, H₂-5 syn) 5.45 (m, H₂-17 syn;H₂-17 anti) 6.50 (s, —OH) 7.25 (d, J=2.57 Hz, H-9 anti) 7.30 (s, H-14syn; H-14 anti) 7.43-7.50 (m, H-11 syn; H-11 anti) 7.70 (d, J=2.57 Hz,H-9 syn) 8.15 (d, J=9.19 Hz; H-12 syn, H-12 anti) 8.25 (s, —CH═N anti)9.00 (s, —CH═N syn).

Mass m/z: 463 (M⁺16) 419 (15) 407 (25) 390 (43) 346 (100) 318 (10).

7-t-butoxyiminomethyl-10-methoxycamptothecin (CPT 220);

m.p.: 250° C. dec.

¹H NMR (DMSO-d₆) 0.88 (t, J=7.35 Hz, H₃-18) 1.47 (s, 3 —CH₃) 1.80-1.93(m, H₂-19) 3.95 (s, —OCH₃ anti) 3.98 (s, —OCH₃ syn) 5.17 (s, H₂-5 anti)5.30-5.45 (m, H₂-5 syn; H₂-17 syn; H₂-17 anti) 6.50 (s, —OH) 7.29 (s,H-14) 7.56 (dd, J=9.19 Hz; J=2.57 Hz; H-11) 7.90 (d, J=2.57 Hz; H-9)8.12 (d, J=9.19 Hz; H-12) 8.39 (s, —CH═N anti) 9.33 (s, —CH═N syn).

Mass m/z: 477 (M56, M) 421 (74) 404 (100) 392 (66) 360 (18.5) 303 (6)274 (7.5).

7-p-nitrobenzyloxyiminomethylcamptothecin (CPT 177);

7-p-methylbenzyloxyiminomethylcamptothecin (CPT 178)

m.p. 203° C. dec.

7-methoxyiminomethylcamptothecin (CPT 179) m.p. 230° C. dec.

7-methoxyiminomethyl-10-hydroxycamptothecin (CPT 211);

m.p.: 268° C. dec.

¹H NMR (DMSO-d₆) δ=0.87 (t, J=7.35 Hz, H₃-18) 1.80-1.90 (m, H₂-19) 4.13(s, —OCH₃) 5.32 (s, H₂-5) 5.41 (s, H₂-17) 6.50 (s, —OH) 7.26 (s, H-14)7.47 (dd, J=9.19 Hz; J=2.56 Hz, H-11) 7.75 (d, J=2.56 Hz, H-9) 8.08 (d,J=9.19 Hz, H-12) 9.04 (s, —CH═N).

7-pentafluorobenzyloxyiminomethylcamptothecin (CPT 182)

m.p. 200° C. dec.

7-carboxymethoxyiminomethylcamptothecin (CPT 183);

7-(carboxydimethylmethoxy)iminomethylcamptothecin;

m.p.: 193° C. dec.

¹H NMR (CDCl₃) δ=1.02 (t, J=7.35 Hz, H₃-18) 1.69 (s, —CH₃) 1.72 (s,—CH₃) 1.81-1.95 (m, H₂-19) 3.60 (s, —OH) 5.24 (d, J=16.55 Hz, H-17A)5.32 (s, H₂-5) 5.65 (d, J=16.55 Hz, H-17B) 7.64 (s, H-14) 7.67 (ddd,J=6.99 Hz; J=8.47 Hz; J=1.47 Hz, H-11) 7.80 (ddd, J=6.99 Hz; J=8.47 Hz;J=1.47 Hz, H-10) 8.10-8.16 (m, H-9; H-12) 9.10 (s, —CH═N).

7-(ter-butoxycarbonyl-2-propoxy)iminomethylcamptothecin (CPT 224);

m.p.: 180° C. dec.

¹H NMR (DMSO-d₆) δ=0.88 (t, J=7 Hz, H₃-18) 1.44 (s, 3 —CH₃) 1.60 (s,2—CH₃) 1.80-1.92 (m, H₂-19) 5.27 (s, H₂-5) 5.43 (s, H₂-17) 6.53 (s, —OH)7.35 (s, H-14) 7.76 (ddd, J=8.46 Hz; J=8.46 Hz; J=1.47 Hz, H-11) 7.92(ddd, J=8.46 Hz; J=8.46 Hz; J=1.47 Hz, H-10) 8.23 (dd, J=8.46 Hz; J=1.47Hz, H-12) 8.65 (dd, J=8.46 Hz; J=1.47 Hz, H-9) 9.20 (s, —CH═N).

Mass m/z: 534 (M+1 3) 477 (29) 374 (55) 273 (10) 57 (100) 41(57).

7-p-phenylbenzyloxyiminomethylcamptothecin (CPT 187)

m.p. 200-202° C. dec.

7-oxiranylmethoxyiminomethylcamptothecin (CPT 213);

¹H NMR (CDCl₃) δ=0.87 (t, J=7 Hz, H₃-18) 0.80-2.00 (m, J=7 Hz, H₂-19)2.80 (1H, m, —CH₂—O) 3.05 (1H, m, —CH₂—O) 3.40 (m, —CH—O) 3.75 (s, —OH)4.30(1H, m, —CH₂—O—N) 4.73 (1 H, m, —CH₂—O—N) 5.33 (d, J=16 Hz, H-17A)5.45 (s, H₂-5) 5.75 (d, J=16 Hz, H-17B) 7.70 (s, H-14) 7.75 (m, H-11)7.85 (m, H-10) 8.15-8.35 (m, H-9; H-12) 9.12 (s, —CH═N).

7-(2-amino)ethoxyiminomethylcamptothecin (CPT 188); m.p. 220° C. dec.

7-(4-pyridyl)methoxyiminomethylcamptothecin (CPT 189) m.p. 220° C. dec,mass m/z M⁺482

7-[(N-methyl)-4-pyperidinyl]methoxyiminomethylcamptothecin (CPT 190)m.p. 185-190° C. dec, mass m/z M⁺502

7-ethoxyiminomethylcamptothecin;

7-isopropyloxyimiminomethylcamptothecin

7-(2-methylbutoxy)iminomethylcamptothecin;

7-cyclohexyloxyiminomethylcamptothecin;

7-cyclohexylmethoxyiminomethylcamptothecin;

7-cyclooctyloxyiminomethylcamptothecin;

7-cyclooctylmethoxyiminomethylcamptothecin;

7-(1-adamantyloxy)iminomethylcamptothecin;

7-(1-adamantylmethoxy)iminomethylcamptothecin;

7-phenoxyiminomethylcamptothecin (CPT 223);

¹H NMR (DMSO-d₆) δ=0.89 (t, J=7.35 Hz, H3-18) 1.81-1.95 (m, H₂-19) 5.25(s, H₂-5 anti) 5.42 (s, H₂-17 anti) 5.45 (s, H₂-5 syn) 5.52 (s, H₂-17syn) 6.56 (s, —OH) 7.15-7.55 (m, 5Ar; H-14) 7.83 (m, H-11) 7.96 (m,H-10) 8.28 (dd, J=8.09 Hz; J=1.10 Hz, H-12) 8.73 (dd, J=8.09 Hz; J=1.10Hz, H-9) 8.92 (s, —CH═N anti) 9.84 (s, —CH═N syn). Mass m/z: 467 (M⁺ 33)373 (100) 329 (62) 314 (72) 273 (62) 244 (52) 135 (38) 57 (25) 43 (39).

7-(2-naphthyloxy)iminomethylcamptothecin;

7-(9-anthrylmethoxy)iminomethylcamptothecin;

7-[2-(2,4-difluorophenyl)ethoxy]iminomethylcamptothecin;

7-(4-t-butylbenzyloxy)iminomethylcamptothecin;

7-triphenylmethoxyiminomethylcamptothecin (CPT 192) m.p. 140° C. dec;

7-(2-N,N-dimethylaminoethoxy)iminomethylcamptothecin (CPT 197);

7-[N-(4-aminobutyl)-2-aminoethoxy]iminomethylcamptothecin;

7-[N-[N-(3-amino-1-propyl)-4-amino-1-butyl]-3-aminopropoxyl]iminomethylcamptothecin;

7-[2-(1-uracyl)ethoxyliminomethylcamptothecin (CPT 199);

m.p.: 197-200° C. dec.

¹H NMR (DMSO-d₆) δ=0.88 (t, J=7.35 Hz, H₃-18) 1.80-1.95 (m, H₂-19) 3.90(t, J=6 Hz, —CH₂N anti) 4.15 (t, J=6 Hz, —CH₂N syn) 4.35 (t, J=6 Hz,—CH₂O anti) 4.58 (t, J=6 Hz, —CH₂ O syn) 5.00 (d, J=8 Hz, H-5 U anti)5.35-5.50 (m, H₂-5 anti; H₂-5 syn; H₂-17 anti; H₂-17 syn) 5.55 (d, J=8Hz, H-5 U syn) 6.55 (s, —OH) 7.15 (d, J=8 Hz, H-6 U anti) 7.40 (s, H-14)7.64 (d, J=8 Hz;, H-6 U syn) 7.70-7.82 (m, H-10 syn; H-10 anti)7.85-8.00 (m, H-11 syn; H-11 anti; H-12 anti) 8.23 (m, H-12 syn; H-9anti) 8.48 (s, —CH═N anti) 8.60 (dd, J=8.46 Hz; J=1.47 Hz, H-9 syn) 9.35(s,—CH═N syn) 11.3 (br s, NH U).

7-[2-(4-morpholininyl]ethoxy]iminomethylcamptothecin (CPT 210);

m.p.: 158-160° C. dec.

¹H NMR (CDCl₃) δ=1.06 (t, J=7.35 Hz, H₃-18) 1.84-2.00 (m, H2-19) 2.62(t, J=4.78 Hz, —CH₂-N morf.) 2.87 (t, J=5.52 Hz, —CH₂—N) 3.60 (s, —OH)3.79 (t, J=4.78 Hz, —CH₂—O morf.) 4.59 (t, J=5.52 Hz, —CH₂—O) 5.33 (d,J=16.18 Hz, H-17A) 5.45 (s, H₂-5) 5.77 (d, J=16.18 Hz; H-17B) 7.69 (s,H-14) 7.73 (ddd, J=1.47 Hz; J=8.46 Hz; J=8.46 Hz, H-11) 7.87 (ddd,J=1.47 Hz; J=8.46 Hz; J=8.46 Hz, H-10) 8.19-8.31 (m, H-9; H-12) 9.12 (s,—CH═N).

Mass m/z: 504 (M⁺ 4) 373 (23) 329 (26) 272 (18) 244 (20) 216 (13) 100(100).

7-(6-uracyl)methoxyiminomethylcamptothecin;

7-(4-hydroxybutoxy)iminomethylcamptothecin;

7-(2-thienyl)methoxyiminomethylcamptothecin;

7-(4-thiazolyl)methoxyiminomethylcamptothecin;

7-(6-D-galactosyloxy)iminomethylcamptothecin;

7-(6-D-glucosyloxy)iminomethylcamptothecin;

7-(6-D-glucosyloxy)iminomethylcamptothecin (CPT 216); m.p.: 210° C. dec.

¹H NMR (DMSO-d₆) δ=0.85 (t, J=7.3 Hz, H₃-18) 1.75-1.95 (m, H₂-19)3.50-5.00 (m, 10H galact.) 5.35 (s, H₂-5) 5.45 (s, H₂-17) 6.25 (d, —OHgalact.) 6.55 (s, —OH) 6.65 (d, —OH galact.) 7.35 (s, H-14) 7.80 (m,H-10) 7.98 (m,; H-11) 8.25 (dd, J=8.47 Hz; J=1.46 Hz, H-12) 8.60 (dd,J=8.47 Hz; J=1.46 Hz, H-9) 9.35 (s, —CH═N).7-(1,2:3,4-di-O-isopropylydene-D-galactopyranosyloxy)iminomethylcamptothecin(CPT 215);

¹H NMR (DMSO-d₆) δ=0.87 (t, J=7.30 Hz, H₃-18) 1.30-1.45 (m, 4—CH₃)3.90-4.70 (m, H₂-6′; H-5′; H-4′; H-3′; H-2′) 1.80-1.93 (m, H₂-19) 5.35(s, H2-5) 5.45 (s, H₂-17) 5.60 (d, J=5.52 Hz, H-1′) 6.52 (s, —OH) 7.35(s, H-14) 7.75 (m, H-10 syn; H-10 anti) 7.90 (m, H-11 syn; H-11 anti)8.05 (dd, J=8.47 Hz; J=1.47 Hz, H-12 anti) 8.20 (m, H-12 syn; H-9 anti)8.50 (s, —CH═N anti) 8.65 (dd, J=8.47 Hz; J=1.47 Hz; H-9 syn) 9.40 (s,—CH═N syn).

Mass m/z: 634 (M+1 13) 576 (10) 486 (18) 347 (35) 329 (45) 314 (49) 302(28) 246 (100) 242 (55) 187 (26).

7-(1-benzyloxyimino)ethylcamptothecin (CPT 186);

7-[1(-t-butoxyimino)ethyl]camptothecin.

EXAMPLE 3 7-benzoylcamptothecin (CPT 170)

Sulfuric acid conc. (0.17 ml) and benzaldehyde (304 mg, 2.87 mmoles)were dropped into a suspension of camptothecin (200 mg, 0.57 mmoles) inCH₃COOH (0.8 ml) and water (0.8 ml). The reaction mixture was cooleddown to 0° C. and 80% t-butyl peroxide (128 mg, 1.14 mmol) and asolution of FeSO₄ (317 mg, 1.14 mmol) in water (0,56 ml) weresubsequently added.

After stirring overnight at room temperature, water was added, aprecipitate was obtained, which was filtered under vacuum. The motherliquors were extracted with methylene chloride (3 times); the organicphases were dried over Na₂SO₄, filtered and evaporated under vacuum. Thesolid thus obtained was gathered with the precipitate, which wasseparated before. The product was purified by means of flashchromatography on silica gel using as eluant a mixture of methylenechloride/methanol 98/2. 90 mg (0.2 mmoles) of product were obtained.

Yield 35%

¹H-NMR (300 MHz; DMSO-d₆): δ: 0.9 (t, 3H H3-18), 1.85 (m, 2H,H2-19), 5(s, 2 H,H2-5), 5.4(2H,H2-5), 5.4 (s, 2H H2-17), 6.6(s, −1H OH), 7.4(s1H,H14), 7.55-7.85 (m, 5H,H1-10,H-11,3Ar), 7.95-8 (m, 3H-H12 2Ar), 8.3(dd, 1H-H-9).

EXAMPLE 4 7-[α-(hydroxyimino)benzyl]camptothecin (CPT 185);

A solution of 7-benzoylcamptothecin (50 mg, 0.11 mmoles), hydroxylaminehydrochloride (24 mg, 0.33 mmoles), pyridine (1.4 ml) in 10 ml ofethanol was prepared and left 24 hours to reflux. The solvent waseliminated under vacuum. The product was purified by means of flashchromatography on silica gel using a mixture of methylenechloride/methanol 98/2 as eluant. 25 mg of a yellow solid were obtained.

Yield 48%

The obtained product is constituted of a mixture of the two syn and antiisomers (isomer A: Rf 0.35; isomer B, Rf: 0.31 on silica gel Merck 60F₂₅₄, eluant methylene chloride/methanol 95/5).

¹H-NMR (300 MHz; DMSO-d₆): δ: 0.9(t, H3-18A+H3-18B), 1.86 (m,H2-19A+H2-19B) 4.8 (m, H2-5A+H2-5B), 5.85 (s, H2-17B), 6.55 (s, —OH B),7.60 (s OH A), 7.35-7.55 (m, Ar A+ArB+H-10A+H-10B+H-11A+H-11B+H-14A+H-14B) 7.6-7.7 (m, H-12A+H-12B).

EXAMPLE 5 7-phenyliminomethylcamptothecin (CPT 154)

100 mg (0.26 mmoles) of 7-formylcamptothecin, dissolved into 20 ml ofmethylene chloride, and 25 μl (0.26 mmoles) of aniline, dissolved into0.5 ml of methylene chloride, were added to a suspension of ytterbiumtriphlate (16.5 mg. 0.026 mmoles, 10% mol) in 5 ml of methylene chloridecontaining MS 4A and were left 3.5 hours under stirring at room T, thenthe solvent was evaporated under vacuum. The product was purified bymeans of flash chromatography on silica gel using a mixture of methylenechloride/methanol 98/2 as eluant. 60 mg of a yellow solid were obtained.

Yield 51%

m.p.: 255-258° C. dec

¹H-NMR (300 MHz; DMSO-d₆): δ: 0.8 (t, 3H H3-18), 1.75 (m, 2H,H2-19),5.35 (s, 2H,H2-5), 5.5 (s, 2H H2-17), 6.45 (s, −1H OH), 7.25-7.35 (m, 2HH1-Ar+H-14), 7.4-7.5 (m,4H Ar), 7.75 (1H,ddd, H-11) 7.85 (ddd, 1H-H10),8.2 (dd, 1H-H-12) 8.9 (dd, 1H, H-9), 9.6 (s, 1H, CH═N).

Following the same procedure the following compounds were prepared:

7-cyclohexyliminomethylcamptothecin (CPT156);

7-p-nitrophenyliminomethylcamptothecin (CPT 160), m.p. 260-265° C. dec;

7-(4-hydroxy)butyliminomethylcamptothecin (CP 169) m.p. 140° C. dec;

7-dimethylaminoethyliminomethylcamptothecin (CPT 171);

7-benzyliminomethylcamptothecin (CPT 175);

7-t-butyliminomethylcamptothecin;

7-allyliminomethylcamptothecin;

7-(2-thienyl)iminomethylcamptothecin;

7-(4-amino)butyliminomethylcamptothecin;

7-(3-aminopropyl-4-aminobutyl-3-aminopropyl)iminomethylcamptothecin;

7-(2-anthrylmethyl)iminomethylcamptothecin;

7-(6-D-galactosyl)iminomethylcamptothecin;

7-(2-quinolylmethyl)iminomethylcamptothecin.

EXAMPLE 6 7-(benzoyloxyiminomethylmethyl)camptothecin (CPT 191)

A solution of benzoyl chloride (0.16 ml, 1.4 mmoles) in 5 ml of pyridinewas prepared and 500 mg (1.3 mmoles) of 7-hydroxyiminomethylcamptothecinwere added and left overnight under stirring at room temperature. Afterevaporating pyridine under vacuum, a solution of sodium bicarbonate wasadded and it was extracted three times with methylene chloride. Afterdrying with sodium sulfate and filtration, the solvent was evaporatedoff. The product was purified by means of flash chromatography on silicagel using a mixture of methylene chloride/methanol 98/2 as eluant. 200mg (0.04 mmoles) of a yellow solid were obtained.

Yield 32%.

m.p.: 210° C. dec

¹H-NMR (300 MHz; DMSO-d₆): δ: 0.8(t. H3-), 1.8 (m, H2) 5.45 (s, H2-5),5.55 (s, H2-17), 6.6 (s, 1H —OH), 7.3 (s 1H, H-14), 7.75-8 (m, 5HH-10+H-11+3Ar) 8.25 (m, 2H, 2Ar) 8.3 (dd, 1H, H-12) 8.75 (dd, 1H, H-9),10.05 (s, 1H, CH═N).

Following the same procedure the following compounds were prepared:

7-p-nitrobenzoyloxyiminomethylcamptothecin

7-p-cyanobenzoyloxyiminomethylcamptothecin

7-p-tolylsulfonyloxyiminomethylcamptothecin

EXAMPLE 7 7-t-butoxyiminomethylcamptothecin N-oxide (CPT 198)

7-t-butoxyiminomethylcamptothecin (30 mg, 0.067 mmol) was dissolved inacetic acid (5.2 ml) and 30% hydrogen peroxide was added. The mixturewas heated at 70-80° C. for 9 hours, condensed to about one third andthe residue was poured into ice-water. The precipitate material wascollected by suction and purified by flash chromatography using amixture of hexane/ ethyl acetate 1/1 as eluent to afford7-t-butoxyiminomethylcamptothecin N-oxide as a yellow power. (15.5 mg).Yield 50%

m.p.: 185-190° C. dec.

¹H NMR (DMSO-d₆) δ=0.87 (t, J=7 Hz, H₃-18) 1.48 (s, 3 —CH₃) 1.76-1.95(m, H₂-19) 5.37 (s, H₂-5) 5.42 (s, H₂-17) 6.60 (s, —OH) 7.85-8.00 (m,H-10; H-11) 8.15 (s, H-14) 8.65-8.75 (m, H-9; H-12) 9.2 (s, —CH═N).

According to the same procedure the following compounds were prepared:

7-methoxyiminomethylcamptothecin N-oxide (CPT 208)

¹H NMR (DMSO-d₆) δ=0.87 (t, J=7.35 Hz, H₃-18) 1.78-1.93 (m, H₂-19) 4.12(s, —OCH₃) 5.35 (s, H₂-5) 5.43 (s, H₂-17) 6.54 (s, —OH) 7.84-8.00 (m,H-10; H-11) 8.11 (s, H-14) 8.68-8.73 (m, H-9; H-12) 9.21 (s, —CH═N).

7-(carboxydimethylmethoxy)iminomethylcamptothecin N-oxide

7-(hydroxymethyldimethylmethoxy)iminomethylcamptothecin N-oxide.

EXAMPLE 8 7-p-nitrobenzyloxyiminomethylcamptothecin (CPT177)

To a suspension of 7-hydroxyiminomethylcamptothecin (40 mg, 0,102 mmol)and sodium carbonate (10.9 mg, 0.102 mmol) in ethanol (4 ml),4-nitrobenzylbromide (22 mg, 0.102 mml) was added and the mixture wasrefluxed for 2.5 hours. The solvent was evaporated under reducedpressure and the residue was purified by flash chromatography using amixture of hexane/ethyl acetate 3/7 as eluent to afford 10.5 mg of7-p-nitrobenzyloxyiminomethylcamptothecin.

Yield 20%

¹H NMR (DMSO-d₆) δ=0.88 (t, J=7 Hz, H₃-18) 1.80-1.92 (m, H₂-19) 5.23 (s,CH₂—O) 5.45(s, H₂-5) 5.57 (s, H2-17) 6.55 (s, —OH) 7.35 (s, H-14)7.75-7.95 (m, 2Ar; H-10; H-11) 8.2-8.4 (m, 2Ar; H-12) 8.65 (dd, J=8.46Hz; J=1.47 Hz, H-9) 9.50 (s, —CH═N).

According to the same procedure the following compounds were prepared:

7-p-methylbenzyloxyiminomethylcamptothecin (CPT178) m.p 203° C. dec.

7-pentafluorobenzyloxyiminomethylcamptothecin (CPT182) m.p. 200° C. dec.

What is claimed is:
 1. A compound of tormula (I)

wherein: R₁ is a —C(R₅)═N—O_((n))R₄ group, wherein R₄ is hydrogen or aC₁-C₈ linear or branched alkyl or C₁-C₈ linear or branched alkenyl groupor C₃-C₁₀ cycloalkyl, or (C₃-C₁₀) cycloalkyl-(C₁-C₈) linear or branchedalkyl group, or C₆-C₁₄ aryl, or (C₆-C₁₄) aryl-(C₁-C₈) linear or branchedalkyl group, or a heterocyclic or heterocyclo-(C₁-C₈) linear or branchedalkyl group, said heterocyclic group containing at least a heteroatomselected from the group consisting of nitrogen atom, optionallysubstituted with a (C₁-C₈) alkyl group, and/or oxygen and/or sulfur;said alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aryl-alkyl,heterocyclic or heterocyclo alkyl groups, being optionally substitutedwith one or more groups selected from the group consisting of: halogen,hydroxy, keto, C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, cyano, nitro, —NR₆R₇,wherein R₆ and R₇, the same or different between them, are hydrogen,(C₁-C₈) linear or branched alkyl; the —COOH group or a pharmaceuticallyacceptable ester thereof; or the —CONR₈R₉ group, wherein R₈ and R₉, thesame or different between them, are hydrogen, (C₁-C₈) linear or branchedalkyl; phenyl; or R₄ is a (C₆-C₁₀) aroyl or (C₆-C₁₀) arylsulfonyl group,optionally substituted with one or more groups selected from the groupconsisting of: halogen, hydroxy, C₁-C₈ linear or branched alkyl, (C₁-C₈)linear or branched alkoxy, phenyl, cyano, nitro, —NR₁₀R₁₁, wherein R₁₀and R₁₁, the same or different between them are hydrogen, C₁-C₈ linearor branched alkyl; or R₄ is a polyaminoalkyl group; n is the number 1;R₅ is hydrogen, C₁-C₈ linear or branched alkyl, C₁-C₈ linear or branchedalkenyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀) cycloalkyl-(C₁-C₈) linear orbranched alkyl, C₆-C₁₄ aryl, (C₆-C₁₄) aryl-(C₁-C₈) linear or branchedalkyl; R₂ and R₃, the same or different between them are hydrogen,hydroxy, C₁-C₈ linear or branched alkoxy; their N₁-oxides, their singleisomers, their possible enantiomers, diastereoisomers and relativeadmixtures, the pharmaceutically acceptable salts thereof and theiractive metabolites; with the proviso that when R₅, R₂ and R₃ arehydrogen, then R₄ is different from hydrogen.
 2. A compound, selectedfrom the group consisting of: 7-methoxyiminomethylcamptothecin;7-methoxyiminomethyl-10-hydroxycamptothecin;7-(ter-butoxycarbonyl-2-propoxy)iminomethylcamptothecin;7-ethoxyiminomethylcamptothecin; 7-isopropoxyiminomethylcamptothecin;7-(2-methylbutoxy)iminomethylcamptothecin;7-t-butoxyiminomethylcamptothecin;7-t-butoxyiminomethyl-10-hydroxycamptothecin;7-t-butoxyiminomethyl-10-methoxycamptothecin;7-(4-hydroxybutoxy)iminomethylcamptothecin;7-triphenylmethoxyiminomethylcamptothecin;7-carboxymethoxyiminomethylcamptothecin;7-(2-amino)ethoxyiminomethylcamptothecin;7-(2-N,N-dimethylamino)ethoxyiminomethylcamptothecin;7-allyloxyiminomethylcamptothecin;7-cyclohexyloxyiminomethylcamptothecin;7-cyclohexylmethoxyiminomethylcamptothecin;7-cyclooctyloxyiminomethylcamptothecin;7-cyclooctylmethoxyiminomethylcamptothecin;7-benzyloxyiminomethylcamptothecin;7-[(1-benzyloxyimino)-2-phenylethyl]camptothecin;7-(1-benzyloxyimino)ethylcamptothecin; 7-phenoxyiminomethylcamptothecin;7-(1-t-butoxyimino)ethylcamptothecin;7-p-nitrobenzyloxyiminomethylcamptothecin;7-p-methylbenzyloxyiminomethylcamptothecin;7-pentafluorobenzyloxyiminomethylcamptothecin;7-p-phenylbenzyloxyiminomethylcamptothecin;7-[2-(2,4-difluorophenyl)ethoxy]iminomethylcamptothecin;7-(4-t-butylbenzyloxy)iminomethylcamptothecin;7-(1-adamantyloxy)iminomethylcamptothecin;7-(1-adamantylmethoxy)iminomethylcamptothecin;7-(2-naphthyloxy)iminomethylcamptothecin;7-(9-anthrylmethoxy)iminomethylcamptothecin;7-oxiranylmethoxyiminomethylcamptothecin;7-(6-uracyl)methoxyiminomethylcamptothecin;7-[2-(1-uracyl)ethoxy]iminomethylcamptothecin;7-(4-pyridyl)methoxyiminomethylcamptothecin;7-(2-thienyl)methoxyiminomethylcamptothecin;7-[(N-methyl)-4-piperidinyl]methoxyiminomethylcamptothecin;7-[2-(4-morpholininyl]ethoxy]iminomethylcamptothecin;7-(benzoyloxyiminomethyl)camptothecin;7-[(1-hydroxyimino)-2-phenylethyl)camptothecin;7-ter-butyloxyiminomethylcamptothecin N-oxide;7-methoxyiminomethylcamptothecin N-oxide.
 3. A compound, selected fromthe group consisting of:7-[N-(4-aminobutyl)-2-aminoethoxy]iminomethylcamptothecin;7-[N-[N-(3-amino-1-propyl)-4-amino-1-butyl]-3-aminopropyl)iminomethyl-camptothecin.4. Compound according to claim 1, which is7-(t-butoxy)iminomethylcamptothecin.
 5. Compound according to claim 1,which is 7-benzyloxyiminomethylcamptothecin.
 6. A process for thepreparation of the compounds of claim 1, comprising the reaction of acompound of formula (Ia)

wherein R₁ is the group —C(R₅)═O, and R₅ is as defined for the formula(I), R₂ and R₃ are as defined in formula (I), with the compound offormula (IIa) R₄O—NH₂, wherein R₄ is as above defined, to give compoundsof formula (I), wherein R₁ is the group —C(R₅)═N—OR₄, R₄ is defined asin formula (I), except aroyl and arylsulfonyl.
 7. Process according toclaim 6, wherein the molar ratio between compound of formula (Ia) andcompound of formula (IIa) is comprised between 1:3 and 3:1.
 8. Processfor the preparation of the compounds of the claim 1, that comprises thereaction of a compound of formula (Ia)

wherein R₁ is the group —C(R₅)═N—OH, and R₅ is as defined for formula(I), R₂ and R₃ are as defined in formula (I), with a halide R₄—X,wherein X is a halogen and R₄ is as above defined, to give compounds offormula (I), wherein R₁ is the group —C(R₅)═N—OR₄, R₄ is defined as informula (I), except aroyl and arylsulfonyl.
 9. Process for thepreparation of the compounds of claim 1, wherein R₄ is aroyl orarylsulfonyl, comprising the reaction of a compound of formula (Ia)

wherein R₁ is the group —C(R₅)═N—OH, and R₅ is as defined for formula(I), R₂ and R₃ are as defined in formula (I), with an acyl chlorideR₄—COCl, wherein R₄ is aroyl or arylsulfonyl as above, to give compoundsof formula (I), wherein R₁ is the group —C(R₅)═N—OR₄, R₄ is aroyl orarylsulfonyl.
 10. Pharmaceutical composition comprising atherapeutically effective amount of at least a compound of claim 1, inadmixture with pharmaceutically acceptable vehicles and excipients. 11.Pharmaceutical composition comprising a therapeutically effective amountof at least a compound of claim 1, in admixture with pharmaceuticallyacceptable vehicles and excipients in combination with other activeingredients.
 12. Pharmaceutical composition according to claim 11wherein said other active ingredient is an antitumoral.
 13. Compounds offormula (Ia)

wherein: R₁ is a group —C(R₅)═N—OR₄, wherein R₄ is hydrogen; or a group(C₆-C₁₀) aroyl or arylsulfonyl, optionally substituted with one or moregroups selected from the group consisting of: halogen, hydroxy, C₁-C₈linear or branched alkyl, C₁-C₈ linear or branched alkoxy, phenyl,cyano, nitro, —NR₁₀R₁₁, wherein R₁₀ and R₁₁, the same or differentbetween them, are hydrogen, C₁-C₈ linear or branched alkyl; R₂ and R₃,the same or different between them are hydrogen, hydroxy, C₁-C₈ linearor branched alkoxy.
 14. A method of treating tumors comprisingadministering to a patient in need of same an effective amount of acompound of claim 1, 2, 3, 4 or
 5. 15. A method of treating a viralinfection comprising administering to a patient an anti-viral effectiveamount of a compound of claim 1, 2, 3, 4 or
 5. 16. A method of treatinga falciparum parasite comprising administering to a patient an effectiveamount of a compound of claim 1, 2, 3, 4 or
 5. 17. A compound of claim 1wherein the single isomer is the syn or anti isomer of the—C(R₅)═N—O_((n))R₄ group.